An Activity‐Based Probe Targeting Non‐Catalytic, Highly Conserved Amino Acid Residues within Bromodomains

Bromodomain‐containing proteins are epigenetic modulators involved in a wide range of cellular processes, from recruitment of transcription factors to pathological disruption of gene regulation and cancer development. Since the druggability of these acetyl‐lysine reader domains was established, effo...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2019-01, Vol.58 (4), p.1007-1012
Main Authors: D'Ascenzio, Melissa, Pugh, Kathryn M., Konietzny, Rebecca, Berridge, Georgina, Tallant, Cynthia, Hashem, Shaima, Monteiro, Octovia, Thomas, Jason R., Schirle, Markus, Knapp, Stefan, Marsden, Brian, Fedorov, Oleg, Bountra, Chas, Kessler, Benedikt M., Brennan, Paul E.
Format: Article
Language:English
Subjects:
Acetylation
activity-based protein profiling
Amino Acid Sequence
Amino acids
Binding Sites
bromodomain
Cancer
Carbamates - chemistry
Catalysis
chemical proteomics
Communication
Communications
Conserved Sequence
covalent probes
Disruption
Domains
epigenetics
Gene expression
Gene regulation
Histones - chemistry
Lysine
Lysine - chemistry
Modulators
Molecular Docking Simulation
Protein Binding
Protein Domains
Proteins
Pyridazines - chemistry
Transcription factors
Triazoles - chemistry
Tyrosine
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Summary:Bromodomain‐containing proteins are epigenetic modulators involved in a wide range of cellular processes, from recruitment of transcription factors to pathological disruption of gene regulation and cancer development. Since the druggability of these acetyl‐lysine reader domains was established, efforts were made to develop potent and selective inhibitors across the entire family. Here we report the development of a small molecule‐based approach to covalently modify recombinant and endogenous bromodomain‐containing proteins by targeting a conserved lysine and a tyrosine residue in the variable ZA or BC loops. Moreover, the addition of a reporter tag allowed in‐gel visualization and pull‐down of the desired bromodomains. Bromodomain‐containing proteins: Since the druggability of these acetyl‐lysine reader domains was established, efforts were made to develop potent and selective inhibitors across the entire family. Here the development of a small molecule‐based approach to covalently modify recombinant and endogenous bromodomain‐containing proteins by targeting a conserved lysine and a tyrosine residue in the variable ZA or BC loops is reported.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201807825